Paola Toppan

Complete Pathologic Response Following Preoperative Chemoradiation Therapy for Middle to Lower Rectal Cancer Is Not a Prognostic Factor for a Better Outcome

PURPOSEThe aim of this study was to evaluate factors associated with pathologic tumor response following preoperative chemoradiation therapy, and the prognostic impact of pathologic response on overall and disease-free survival.METHODSBetween 1994 and 2002, 132 patients underwent chemoradiation therapy followed by surgery for middle to lower rectal cancer. After excluding 26 cases (metastatic cancer, n = 13; nonradical surgery, n = 6; local excision procedure, n = 4; non-5-fluorouracil-based chemotherapy, n = 2; incomplete data on preoperative chemoradiation therapy regimen used, n = 1), the remaining 106 patients were included in the study. Variables considered were the following: age, gender, tumor location, pretreatment T and N stage, modality of 5-fluorouracil administration, total radiotherapy dose delivered, chemoradiation therapy regimen used (Regimen A: chemotherapy (bolus of 5-fluorouracil and leucovorin, days 1–5 and 29–33) + radiotherapy (45 Gy/25 F/1.8 Gy/F); Regimen B: chemotherapy (5-fluorouracil continuous venous infusion ± weekly bolus of carboplatin or oxaliplatin) + radiotherapy (50.4 Gy/28 F/1.8 Gy/F)), time interval between completion of chemoradiation therapy and surgery, postoperative chemotherapy administration, surgical procedures, pT, pN, and pTNM stage, and response to chemoradiation therapy defined as tumor regression grade, scored from 1 (no tumor on surgical specimen) to 5 (absence of regressive changes). Statistical analysis was performed by means of logistic regression analysis (Cox’s model for overall and disease-free survival).RESULTSMedian age of the 106 patients was 60 (range, 31–79) years and the male:female ratio, 66:40. Median distance of tumor from the anal verge was 6 (range, 1–11) cm. Pretreatment TNM stage, available in 104 patients, was cT3–T4N0, n = 41; cT2N1, n = 9; cT3N1, n = 39; and cT4N1, n = 17. The median radiotherapy dose delivered was 50.4 (range, 40–56) Gy; 58 patients received 5-fluorouracil by continuous venous infusion, and carboplatin with oxaliplatin was added to the chemotherapy schedule in 71 cases. Patients were given Regimen A in 47 cases and Regimen B in 59. The median interval between chemoradiation therapy and surgery was 42.5 (range, 19–136) days, and 94 patients underwent a sphincter-saving procedure. Tumor regression grade, available in 104 cases, was 1, n = 19; 2, n = 18; 3, n = 15; 4, n = 13; and 5, n = 39. At a median follow-up of 42 (range, 1–110) months, 11 patients had died, and 95 were alive. None of the patients had local recurrences, but 13 had distant recurrences. At logistic regression analysis, the chemoradiation therapy regimen used was the only independent predictor of tumor response following preoperative chemoradiation therapy (odds ratio = 0.29, 95% confidence interval = 0.13–0.67, P = 0.003). At Cox’s regression analysis, pretreatment T stage was the only independent prognostic factor for both disease-free survival (relative risk = 7.13, 95% confidence interval = 2.3–21.8, P = 0.001) and overall survival (relative risk = 4.83, 95% confidence interval = 1.1–19.9, P = 0.029).CONCLUSIONSTumor response following preoperative chemoradiation therapy is mainly related to the preoperative regimen used. For patients receiving preoperative chemoradiation therapy, pretreatment T stage, but not tumor response to preoperative chemoradiation therapy, is prognostic for outcome (both disease-free and overall survival).

Relationship between pathologic T-stage and nodal metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer.

BackgroundWe investigated the relationship between pathologic T-stage and mesorectal metastases after preoperative chemoradiotherapy (CRT) for clinical stage II to III rectal carcinoma.MethodsThe records of consecutive patients with clinical stage II to III carcinoma of the mid or low rectum who underwent surgery after CRT were reviewed. Indications for preoperative CRT were cancer up to 11 cm from the anal verge, Eastern Cooperative Oncology Group performance status of 0 to 2, age 18 to 75 years, and clinical tumor-node-metastasis stage II or III.ResultsThe study group consisted of 235 patients (148 men and 87 women; median age, 61 years). The pretreatment tumor-node-metastasis stage was as follows: I, n = 1; II, n = 96; and III, n = 138. Radiotherapy was delivered at a median dose of 50.4 Gy. A pathologic complete response on the rectal wall was found in 24% of patients, and nodal metastases were found in 20% of patients. According to the pT stage, the rate of node positivity was 2% for pT0, 15% for pT1, 17% for pT2, 38% for pT3, and 33% for pT4 cases. At multivariate analysis, the best model for predicting pathologic node involvement included young age, positive pretreatment N status, and pT status. On considering pT stage alone, the odds ratio was in the region of 10 for pT1/2 and >20 for pT3/4 patients.ConclusionsIn patients with pT0 after preoperative CRT for clinical stage II to III mid or low rectal cancer, the risk of nodal metastases is very low. More conservative surgery (local excision) may be considered in these cases.

P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer.

Background Our aim was to ascertain whether or not the response to preoperative chemoradiotherapy for rectal cancer is associated with p27kip1 and p53 protein expression.Methods: Thirty-eight patients (27 male, 11 female) with a mean age of 59 years (age range 33–87) and stage II-III rectal cancer received preoperative chemoradiotherapy (45–50.4 Gy; 5-FU 350 mg/m2/day and leucovorin 10 mg/m2/day). Thirty-one underwent low anterior resection; seven underwent abdominoperineal excision. Endoscopic tumor biopsies, performed before adjuvant therapy, were evaluated for: histologic type, tumor differentiation, mitotic index, and p27kip1 and p53 protein expression which were immunohistochemically determined. p53 expression was graded as: a) absent or present in ≤10% of tumor cells; b) present in 11–25%; c) present in 26–75%; and d) present in >75% of tumor cells. p27kip1 expression was assessed using both light microscopy (percent of stained cells x10 HPF) and cytometry with an image analysis workstation. Tumor response, ascertained with histology, was classified using a scale from 0 (no response) to 6 (complete pathologic response).Results: The mitotic index for the endoscopic biopsies was low in 14 cases, moderate in 17 cases, and high in 7 cases. p53 protein expression was found in 21 (a), 3 (b), 3 (c), and 11 (d) cases. The mean percentage of cells expressing the p27kip1 protein was 34 (range 0–77.14%). A close correlation was found between cytometric and light microscopy findings for p27kip1 (r2 = 0.92, P = .0001). Tumor differentiation was good in 5 cases, poor in 2 cases, and moderate in the remaining 31 cases. While the response to adjuvant therapy was good/complete in 25 (65.78%) cases, it was absent/poor in 13 (34.21%) cases. Univariate analysis associated type of adjuvant therapy (chemoradiotherapy, P = .0428) and p27kip1 protein lower expression (P = .0148) with a poor response to adjuvant treatment. Stepwise linear regression found overexpression of p53 and p27kip1 and young age to be independent variables that were linked to a good response to adjuvant therapy.Conclusions:Lack of p27kip1 and p53 protein expression in rectal cancer is associated with a poor response to preoperative adjuvant therapy.

PREOPERATIVE COMBINED RADIOTHERAPY AND CHEMOTHERAPY FOR MIDDLE AND LOWER RECTAL CANCER: PRELIMINARY RESULTS

Background: Adjuvant treatment for rectal cancer is still controversial. This study reports on overall survival and disease-free survival, toxicity, downstaging, and surgical morbidity in rectal cancer patients who received combined chemoradiation therapy followed by curative surgery.Methods: Between 1993 and 1998, 51 patients (31 males and 20 females; median age, 60 years; range, 33–73 years) underwent chemoradiation therapy followed by radical surgery for middle and lower rectal adenocarcinoma. Criteria for giving preoperative radiotherapy (total 45 Gy in 25 fractions of 1.8 Gy/day for 5 weeks) and chemotherapy (5-fluorouracil 350 mg/m2/day and leucovorin 10 mg/m2/day, bolus on days 1–5 and 29–33) were an age younger than 75 years; an Eastern Cooperative Oncology Group performance status score of 0 to 2; and clinical preoperative stage II–III. Forty-three low anterior and eight abdominoperineal resections were performed. Median follow-up time was 29 (range, 3–63) months.Results: Although grade 3 to 4 toxicity occurred in 14 cases (27.4%), all patients completed the planned adjuvant therapy. At pathology, a complete response was found in eight (15.7%) cases. Of the remaining 43 cases, 22 were stage I, 12 were stage II, and 9 were stage III. Five-year actuarial disease-free survival and overall survival rates were 86.4% and 85.5%, respectively. Whereas no local recurrences were found, 4 patients had distant metastases. Three patients died (1 of cancerrelated causes), 45 are alive and disease free, and 3 are alive with disease.Conclusions: The combined preoperative chemoradiation approach used by us seems to improve the disease-free survival and overall survival of selected patients with rectal cancer. However, a longer follow-up time is required to confirm these preliminary results.

Preoperative combined radiotherapy and chemotherapy for rectal cancer does not affect early postoperative morbidity and mortality in low anterior resection.

PURPOSE: It is not yet known whether preoperative combined radiotherapy and chemotherapy for rectal cancer affects postoperative mortality and morbidity. We therefore evaluated early postoperative complications in patients given adjuvant radiotherapy and chemotherapy before surgery for middle and lower rectal adenocarcinoma. METHODS: Between 1994 and 1998, 41 patients underwent combined preoperative pelvic radiotherapy and chemotherapy at our institution. Most of the patients had 45 Gy (1.8 Gy/day/25 fractions) during five weeks plus 5-fluorouracil (350 mg/m2/day) and low-dose leucovorin (10 mg/m2/day) bolus on Days 1 to 5 and 29 to 33. Surgery was performed four to six weeks after completion of adjuvant therapy. The 41 patients (Group A) were retrospectively compared with 30 patients (Group B) who, in the same period, underwent surgery without preoperative adjuvant therapy. The groups were homogeneous for age, gender, preoperative risk factors, operating surgeon, and pathologic stage. Mean distance of the tumor from the anal verge was shorter in Group A patients (P=0.031). RESULTS: There were seven major postoperative complications in each group. No significant differences were found between the groups for morbidity and mortality rates. Considering all patients, more postoperative complications were found in patients scored as American Society of Anesthesiologists 3, in those with a preoperative hemoglobin value <10 g/dl, and in those without a diverting stoma (P=0.0048,P=0.0453, andP=0.0033, respectively). At multivariate analysis, independent predictors of major complications were American Society of Anesthesiologists score (relative risk, 343;P=0.022), diverting stoma (relative risk, 159;P=0.010), type of surgical procedure (relative risk, 38.9;P=0.048), preoperative hemoglobin value (relative risk, 9.72;P=0.061), and intraoperative blood loss (relative risk, 1;P=0.027). In Group A patients, the absence of diverting stomas was associated with major postoperative complications (P=0.0307), and independent predictors of major complications were American Society of Anesthesiologists score (relative risk, 56;P=0.111) and absence of a diverting stoma (relative risk, 22.42;P=0.222). CONCLUSION: Early postoperative complications after resection for middle and lower rectal adenocarcinoma are affected by intraoperative and preoperative risk factors and absence of diverting stomas, but not by preoperative adjuvant therapy.

Health-related quality of life, faecal continence and bowel function in rectal cancer patients after chemoradiotherapy followed by radical surgery.

PurposeTo evaluate health-related quality of life (HRQOL), faecal continence and bowel function of patients with rectal cancer who underwent preoperative chemoradiotherapy (pCRT) in a cross-sectional setting.MethodsOut of 185 consecutive patients who underwent pCRT for rectal cancer from 1994 to 2004 at a single institution, 101 were eligible for the study. Causes of exclusion were: death (n = 38), not radical surgery or recurrence (n = 21), presence of stoma at the time of the survey (n = 15), lost to follow-up (n = 6) and miscellaneous (n = 4). Eligible patients were asked to complete: the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, the disease specific colorectal module (EORTC QLQ-CR38) and faecal incontinence and bowel function questionnaires. HRQOL outcomes were compared with reference data from the general population, and the association among clinical variables and HRQOL was also investigated with linear regression analyses.ResultsQuestionnaires were completed by 80% of eligible patients. Compared to population-based norms, patients showed clinically meaningful worse outcomes in terms of constipation and diarrhoea. Stool fractionation (p < 0.01) and use of enema/laxative (p < 0.01) were negatively associated with global health status/QOL. Urgency negatively affected physical (p < 0.01), role (p < 0.01) and social functioning (p < 0.01). Sensation of incomplete evacuation negatively affected social functioning (p < 0.01).ConclusionsAlthough HRQOL profile of these patients is broadly similar to that of healthy subjects, there are still important limitations in terms of key symptoms. The use of validated questionnaires is crucial to provide standardised information on relevant health status areas.

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

AbstractPURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites (≥ 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.

Pulmonary lymphangioleiomyomatosis: a case report in postmenopausal woman treated with pleurodesis and progesterone (medroxyprogesterone acetate).

The main problem in the treatment of pulmonary lymphangioleiomyomatosis, which frequently occurs in the reproductive age, is the control of chylothorax and disease progression. We herein report a case of a 62-year-old woman who underwent surgery for recurrent chylothorax. Histologic examination of lung and lymph node biopsies demonstrated lymphangioleiomyomatosis. Thirty-six months after tetracycline pleurodesis and high-dose medroxyprogesterone acetate therapy, the disease was stable and chylothorax effectively controlled. It would therefore appear that hormonal treatment with medroxyprogesterone acetate may be beneficial in postmenopausal women.

Psychological well-being outcomes in disease-free survivors of mid-low rectal cancer following curative surgery.

Objective: The aim of this cross‐sectional study was to evaluate psychological well‐being outcomes in disease‐free survivors who previously underwent radical surgery for rectal adenocarcinoma.

Patient-reported outcomes following preoperative chemoradiotherapy for rectal cancer: A prospective multicenter observational study

4099 Background: Little evidence is available on patient reported outcomes (PROs) following preoperative chemoradiotherapy (CRT) for rectal cancer. Methods: 151 patients with mid-low rectal cancer were enrolled in this study. PROs were evaluated with methodologically sound robust measures. Quality of life was measured with the EORTC QLQ-C30 and its colorectal cancer module (QLQ-CR38). Psychological aspects, fecal incontinence and functional outcomes were measured respectively with the Psychological Well-Being Index (PGWBI) and the Fecal Incontinence Score (FIS) questionnaires. All self-reported questionnaires were completed before CRT (baseline, t0), 3 weeks after the completion of CRT (t1), and then at 6 (t2) and 12 months (t3) after surgery. Socio-demographic and clinical data were also collected. Comparisons were made by repeated measures analysis of variance for each PRO domain. Analysis was planned a priori on most relevant outcomes. A p-value <.01 was considered statistically significant. Results: C...